Liver-specific T regulatory type-1 cells program local neutrophils to suppress hepatic autoimmunity via CRAMP

Cell Rep. 2021 Mar 30;34(13):108919. doi: 10.1016/j.celrep.2021.108919.

Abstract

Neutrophils with immunoregulatory properties, also referred to as type-2 neutrophils (N2), myeloid-derived suppressor cells (MDSCs), or tumor-associated neutrophils (TANs), comprise a heterogeneous subset of cells that arise from unknown precursors in response to poorly understood cues. Here, we find that, in several models of liver autoimmunity, pharmacologically induced, autoantigen-specific T regulatory type-1 (TR1) cells and TR1-cell-induced B regulatory (Breg) cells use five immunoregulatory cytokines to coordinately recruit neutrophils into the liver and program their transcriptome to generate regulatory neutrophils. The liver-associated neutrophils from the treated mice, unlike their circulating counterparts or the liver neutrophils of sick mice lacking antigen-specific TR1 cells, are proliferative, can transfer disease protection to immunocompromised hosts engrafted with pathogenic effectors, and blunt antigen-presentation and local autoimmune responses via cathelin-related anti-microbial peptide (CRAMP), a cathelicidin, in a CRAMP-receptor-dependent manner. These results, thus, identify antigen-specific regulatory T cells as drivers of tissue-restricted regulatory neutrophil formation and CRAMP as an effector of regulatory neutrophil-mediated immunoregulation.

Keywords: B regulatory cells; CRAMP; Interleukins; T regulatory type-1 cells; autoimmune hepatitis; granulocyte colony stimulating factor; myeloid-derived suppressor-like cells; peptide-major-histocompatibility-complex-based nanomedicines; primary biliary cholangitis; tumor growth factor β.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens / metabolism
  • Autoimmunity*
  • B-Lymphocytes, Regulatory / immunology
  • Cathelicidins / metabolism*
  • Cell Polarity / genetics
  • Cytokines / metabolism
  • Gene Expression Regulation
  • Inflammation / pathology
  • Kupffer Cells / metabolism
  • Liver / immunology*
  • Liver / pathology
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mitosis / genetics
  • Myeloid-Derived Suppressor Cells / immunology
  • Neutrophil Infiltration
  • Neutrophils
  • Organ Specificity
  • Phenotype
  • T-Lymphocytes, Regulatory / immunology*
  • Transcription, Genetic

Substances

  • Antigens
  • Camp protein, mouse
  • Cathelicidins
  • Cytokines

Grant support